DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Applicant’s amendment filed 05/02/2023 is acknowledged. Claims 3, 6-13, 19-20, 23, 30, 34, 36-37, and 43-44 have been amended. Claims 4, 14-18, 21-22, 24-29, 31-33, 35, 38-42, and 45-51 have been cancelled. Claims 2-3, 5-13, 19-20, 23, 30, 34, 36-37, and 43-44 are pending in the instant application and the subject of this non-final office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or marked as considered on a provided IDS, they have not been considered.
Information Requirement
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
In response to this requirement, please provide copies of each publication which any of the inventors authored or co-authored and which describe the disclosed subject matter of signatures of PD-1+ CD39+ CD8+ T cells and/or CD26+ CD4+ T cells.
In particular, please provide at least the publicly presented poster(s) corresponding to the abstracts in the Conclusion and any other publicly presented poster or conference talk on the same subject matter and/or CD26+ CD4+ T cells.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Specification
The disclosure is objected to because of the following informalities:
The specification makes reference to multiple “Supplemental” or “Supplementary” figures and tables that have not been identified in the disclosure (e.g., para [0220]).
The description of the figures makes reference to colors (e.g., para [0018-19]); however, the figures are in greyscale.
Para [0241] contains browser executable code. As described in MPEP 608.01(VII), references to websites should be limited to the top-level domain without any prefix such as “http://”.
Appropriate correction is required.
The use of the terms including “Texas red”, which is a trade name or a mark used in commerce, has been noted in this application. Such terms should be accompanied by the generic terminology; furthermore such terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding all claims, the term a “level of … cells” (e.g., “an elevated level of exhausted CD8+ T cells” in claim 2 or “a decreased level of CD26+CD4+ T cells” in claim 19) has been interpreted according to the customary meaning of a concentration, amount, or magnitude of a quantity of cells (Merriam-Webster: pg. 2, Noun, 8 and 9; pg. 10, Noun, 4).
While it is noted the specification provides a definition for “elevated level” in para [0064], such is limited to the context of gene expression and therefore would not be applicable to a level of cells.
Regarding claim 9, the claim recites “the patient is a premenopausal woman”. The term “premenopausal” was interpreted broadly in view of the lack of a limiting definition and the use in the specification to encompass ages below a heuristic threshold of menopausal onset, e.g., the METABRIC definition described in the instant specification that separated premenopausal and postmenopausal patients with a cutoff age of 50 years (para [0200]).
Regarding claim 37, the set of genes in claim 37 is set of non-reference genes of the Oncotype DX Breast Recurrence Score, referred to as “Oncotype Dx® test” or “Oncotype Dx® BRS” in the specification. Accordingly, “intermediate” and “low” were interpreted according to the classifications of the high, low, and intermediate thresholds for the Oncotype Dx test provided in para [0021] of the instant specification. See also para [0201-0204].
See also Cheng (Cheng R, et al. Oncotype DX Breast Recurrence Score Distribution and Chemotherapy Benefit Among Women of Different Age Groups With HR-Positive, HER2-Negative, Node-Negative Breast Cancer in the SEER Database. Front Oncol. 2020 Oct 30;10:1583.; as cited in the IDS dated 05/02/2023), Introduction para. 2, citing Paik (Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004 Dec 30;351(27):2817-26.: Fig. 1: Gene list).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 7, 12, and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 7, 12, and 23, claim 7 recites “wherein the elevated level of exhausted CD8+ T cells comprises an unequally weighted average of the elevated gene expression levels of the genes in Table 1”. Claim 12 recites “wherein the elevated level of exhausted CD8+ T cells comprises an unequally weighted averaged … and wherein the decreased level of CD26+CD4+ T cells comprises an unequally weighted averaged of the decreased gene expression levels …”. Claim 23 recites “wherein the decreased level of CD26+CD4+ T cells comprises an … average … and the increased level of CD26+CD4+ T cells comprises … an average …”.
First, while detection of levels of cells may certainly encompass determining a calculation or measuring gene expression levels indicative of cell levels, it is unclear how the level of the cells (i.e., an amount/concentration of cells) would comprise such an average or how such a mathematical calculation/statistic is intended to be “detected”.
Second, the claims recite “the genes in Table 1” (claims 7 and 12) and/or “the genes in Table 2” (claims 12 and 23). As described in MPEP 2173.05(d): ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
In the instant case, said tables are each a simple a list of genes. As demonstrated by claim 37, such a list may be defined in words. Thus, this is not found to be a case of necessity.
Regarding claim 34, the claim recites “wherein the level is an mRNA expression level or a protein expression level”. However, parent claim 2 recites “detecting an elevated level of exhausted CD8+ T cells”. It is unclear how a level of cells is an mRNA expression level or a protein expression level, rather than is, for example, “determined” by such levels of biomarkers.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 7, 12, and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claims 7, 12, and 23, claim 7 recites “wherein the elevated level of exhausted CD8+ T cells comprises an unequally weighted average of the elevated gene expression levels of the genes in Table 1”. Claim 12 recites “wherein the elevated level of exhausted CD8+ T cells comprises an unequally weighted averaged … and wherein the decreased level of CD26+CD4+ T cells comprises an unequally weighted averaged of the decreased gene expression levels …”. Claim 23 recites “wherein the decreased level of CD26+CD4+ T cells comprises an unequally weighted average … and the increased level of CD26+CD4+ T cells comprises unequally weighted an average …”.
The Applicant’s disclosure lacks sufficient detail to demonstrate possession of the claimed invention, as required under 112(a).
The applicant teaches an exemplary weighting strategy based on the mean Log2 calculation for reach gene (para [0131-132]), providing weights for Table 1 (Fig. 22) and refers to this as the T_EX signature score (para [0132]). The disclosure teaches that Example 1 utilize the 25-gene signature of exhausted CD8+ T Cells to determine overall survival and reduced time to relapse (para [0250]). Likewise, the disclosure teaches the 38-gene signature to identify CD26+CD4+ T cells in Table 2 (para [0249]).
No other weighting schemes were identified in the disclosure for the genes of Table 1; no weighting schemes were described for the genes of Table 2. Nor were subsets of genes utilized in detecting a level of the claimed cells in either Examples 1 and 2.
In contrast to this narrow species described of the entire sets of genes of Tables 1 and 2 and the singular weighting scheme of mean Log2 for Table 1 genes, the claims of “an unequally weighted average” may encompass weights from 0 to any number shy of infinity, such that all weights may be set to zero except for that of a single gene or any number of weights may be non-zero (i.e., effectively 1 to all genes included in the average).
As described above, the disclosure only supports a single unequally weighted average scheme for Table 1. It does not support the broader scope claimed of any unequally weighted average for detecting CD8+ Tex cells nor does it adequately support an unequally weighted average for detecting CD26+CD4+ T cells.
Therefore, claims 7, 12, and 23 lack written description for “unequally weighted average of the … gene expression levels”.
Claim 2-3, 5-13, 19-20, 23, 30, 34, 36-37, and 43-44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for detecting claimed CD8/CD4 T cells subsets in peripheral blood, lymph node, disease-free breast tissue, and tumor samples and administering therapy based on detection in tumor samples based on a like standard control, does not reasonably provide enablement for detecting or administering therapy based on any biological sample relative to any standard control. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Regarding 2-3, 5-13, 19-20, 23, 30, 34, 37, and 43-44, claim 2 recites “detecting an elevated level of exhausted CD8+ T cells relative to a standard control in a biological sample … from the … patient”. Claim 5 recites “A method of treating breast cancer … comprising: detecting an elevated level of [CD8+ Tex], relative to a standard control, in a biological sample obtained from a patient, and administering … an effective amount of a chemotherapeutic …”. Claim 19 recites “A method of detecting CD26+CD4+T cells in a breast cancer patient … comprising detecting: (i) a decreased level of CD26+CD4+ T cells, relative to a control, in biological sample obtained from the … patient …”.
First, these claims are broad. They (aside from claim 36) encompass any type of biological sample that may be obtained from a patient: tumor, whole blood, plasma, urine, hair, saliva, fecal material, etc. The basis for which a standard control is not limited in the claim and the definition in para [0067] is broad (“treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment”), so the increase could be relative to non-disease samples of the individual, an earlier time point, a non-disease sample in the other population, another tissue type, the tissue from another species, etc. Further, all breast cancer patients at all stages and subtypes are encompassed (aside from claims 8, 9, and 30).
Second, the invention is in the class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Third, the instant specification teaches that exhausted CD8+ T cells are enriched in tumor of breast cancer patients (para [0170]), but that PD-1 CD39+ CD8+ T cells were highest in primary tumors, followed by T+ LNs and were rarely detected in PBMCs and never in NCBT (para [0179]). Further detection analyses and characterization that prompt conclusions about treatment utilize tumors (e.g., para [0189-205]).
Likewise, the specification teaches finding increased fractions of CD26- CD4+ T cells were found in breast tumor, in contrast to CD26_high expressing CD4+ T cells in normal, disease-free breast tissues (para [0248]).
Further, in addition to teaching a narrower scope of tissues, the disclosure teaches that the identified T_EX signature indicative of exhausted T cells in breast cancer “shared common features to both those seen in other disease states [including LCMV murine models of T cell exhaustion and those identified in lung cancer and melanoma] and classically defined exhausted T cells” (para [0188]).
Regarding the samples, the prior art teaches unpredictability in the distribution of cells and the ability for detection to meaningfully provide information about the tumor. Huang (Huang Y, et al. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget. 2015 Jul 10;6(19):17462-78) teaches the profiles of T cell subsets in peripheral organs cannot predict that in the tumor microenvironment (pg. 17467, col 1, para 1). Specifically, Huang teaches that all CD4+ T cell subsets in blood had a sharp increase at the early stage [after tumor introduction], then followed by a rapid drop at middle and late cancer stages in two tumor types (pg. 17467, col 1, para 1). Likewise, Huang teaches that all T cell subsets markedly increased in lymph nodes at late stage in one tumor type but not the other tested (pg. 17467, col 1, para 1) and that all CD4+ subsets remained at very low proportions in the spleens of both tumor models, but with varied distributions throughout tumor development (pg. 17467, col 1, para 1).
The prior art similarly teaches that the exhaustion markers PD-1 and CD39 (see para [0180-186]) are taught as virus-specific markers in HCV and HIV. Gupta (Gupta PK, et al. CD39 Expression Identifies Terminally Exhausted CD8+ T Cells. PLoS Pathog. 2015 Oct 20;11(10):e1005177) states: “there was a significant correlation between viral load and the fraction of virus-specific CD8+ T cells that were CD39+ PD-1+ double positive in both HCV and HIV infection” (pg. 5, para 2). Thus, it would be understood by the artisan that there would be a high degree of uncertainty about the specificity of exhausted CD8+ T cells originating from any biological sample compared to any reference, as a breast cancer patient may have comorbid HCV or HIV (or, indeed in view of the broader teaching including LCMV, other viral infections that may become similarly chronic given the cancer or previous cancer treatments).
Similarly, CD26+CD4+ T cells are known in the art to play a role in the migration of T cells, particularly in patients with autoimmune disease. Ohnuma (Ohnuma K, Morimoto C. DPP4 (dipeptidyl-peptidase 4). Atlas of Genetics and Cytogenetics in Oncology and Haematology. 2013 May;(5):301–12) teaches increased numbers of CD4+ CD26+ T cells in inflamed tissues and peripheral blood of patients of autoimmune diseases including multiple sclerosis, Grave's disease, and rheumatoid arthritis (pg. 305, col 1, para 1). Thus, it there would be a high degree of uncertainty about the specificity of CD4 CD26+ T cells in determining a subset of breast cancers as the artisan would recognize that MS, Grave’s and RA may be comorbid with breast cancer.
Some exemplary guidance is provided in para [0067] regarding sources of possible controls; however, guidance on the type of sample was not identified.
Thus, there is a high level of unpredictability in view of the disclosure and state of the prior art given the breadth of samples and standard controls. In particular, for treatment claims 3, 5, 20, and all dependents thereof, there is further uncertainty in view of the prior art’s teachings that both exhausted CD8+ T cells from a non-tumor source and CD26+CD4+ from a non-tumor source may be utilized to detect non-breast cancer conditions that may be comorbid with breast cancer. Balanced only against the high degree of skill in the art, it is held that the amount of experimentation required to utilize the full scope of the claimed invention would be undue.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7, 12, 23, and 34 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claims 7 and 12, parent claim 2 recites “detecting an elevated level of exhausted CD8+ T cells”. Claim 7 recites “wherein the elevated level of exhausted CD8+ T cells comprises an unequally weighted average of the elevated gene expression levels…”. Claim 12 recites “wherein the elevated level of CD8+ T cells comprises an unequally weighted average … and wherein the decreased level of CD26+CD4+ T cells comprises an unequally weighted average …”
Claims 7 and 12 change the scope of claim 2 by attempting to redefine “level of … cells” (i.e., a concentration/amount of cells) to a term that may comprise a mathematical calculation based on gene expression. While it may be understood that a result of a gene expression average (e.g., signature/score) may indicate a level of cells, it itself is not a concentration/amount of cells nor a portion thereof.
By replacing the “cells” with the level comprising an average of gene expression levels, claims 7 and 12 fail to include all the limitations of the claim on which they depend and thus fail to comply with the 112(d) requirements.
Regarding claim 23, parent claim 19 recites “detecting a level of CD26+CD4+ T cells … in a biological sample … or an increased level of CD26+CD4+ T cells in a biological sample …”. Claim 23 recites “the decreased level of CD26+CD4+ T cells comprises an unequally weighted average of the decreased gene expression levels … and … the increased level of CD26+CD4+ T cells comprises an unequally weighted average of the decreased gene expression levels …”.
As above, claim 19 changes the scope of claim 19 by attempting to redefine “level of … cells” (i.e., a concentration/amount of cells) to a term that may comprise a mathematical calculation based on gene expression.
By replacing the “cells” with the level comprising an average of gene expression levels, claim 23 fails to include all the limitations of the claim on which it depends and thus fails to comply with the 112(d) requirements.
Regarding claim 34, parent claim 2 recites “detecting an elevated level of exhausted CD8+ T cells”. Claim 34 recites “wherein the level is an mRNA level or a protein expression level”.
Claim 34 changes the scope of claim 2 by attempting to redefine “a level of cells” to “an mRNA expression level or a protein expression level”. While it may be understood that such a level of cells may be indicated by the level of a biomarker, the claim states that the “the level is an … expression level” (emphasis added).
By replacing the “cells” with the chosen biomarker, claim 34 fails to incorporate all limitations, thereby failing to comply with the requirements of 112(d).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 2-3, 5-13, 19-20, 23, 30, 34, 36-37, and 43-44 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) abstract ideas and natural phenomena. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a process/method.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
Regarding claims 2-3, 6-13, 34, 36-37, the claims recite a method of detecting an elevated level of exhausted CD8+ T cells relative to a control in a sample from a breast cancer patient. Detecting encompasses the abstract idea of a mental process (i.e., observations, evaluations, and judgments), and an elevated level relative to a standard control encompasses a calculation (that may be performed by the human mind). For example, the claim encompasses observing a photo of prepared slides and making a judgement that the “test” sample has a greater amount of exhausted cells than the standard control and/or counting the number of “positive” cells for a marker and subtracting it from a number in the image of a standard control. Thus, the claim is directed to an abstract idea. See MPEP 2106.04(a)(2).
The claims also encompass the natural phenomenon of the correlation between exhausted CD8+ T cell markers (i.e., protein or mRNA markers) and the elevated presence of this class of T cells in patient and/or the elevated presence of exhausted CD8+ T cells and the subtype of breast cancer being detected via the level of the cells. Thus the claim is also directed to a natural phenomenon. See MPEP 2106.04(b)(I).
Claims 7 and 12 recite that the level comprises an unequally weighted average; this also directs the claim to a mathematical calculation abstract idea. It is noted that such may be accomplished by the human mind.
Regarding claim 5, the claims recite a method of treating breast cancer comprising detecting an elevated level of exhausted CD8+ T cells relative to a control in a sample from a breast cancer patient. As above, detecting encompasses the abstract idea of a mental process and/or mathematical calculation. See MPEP 2106.04(a)(2).
The claim also encompasses the same natural phenomena discussed above for exhausted CD8+ T cells. See MPEP 2106.04(b)(I).
Regarding claims 19, 20, 23, and 30, the claims recite a method of detecting CD26+CD4+ T cells relative to a control in a sample from a breast cancer patient. As above, detecting encompasses the abstract idea of a mental process and/or mathematical calculation. See MPEP 2106.04(a)(2).
The claims also encompass the natural phenomenon of the correlation between CD26+CD4+ T cell markers and the presence/absence of this class of T cells in the patient and/or the subtype of breast cancer being detected via the level of the cells. Thus the claim is also directed to a natural phenomenon. See MPEP 2106.04(b)(I).
Claim 23 recites that the level comprises an unequally weighted averages; this also directs the claim to a mathematical calculation abstract idea. It is noted that such may be accomplished by the human mind.
Step 2A, prong 2. Is the judicial exception(s) integrated into a practical application?
Regarding claim 2-3, 6-13, 34, 36-37, claim 2 recites only a detection step, thus encompassing methods with only the judicial exception. Claim 11 recites a further detection step, which likewise encompasses the same judicial exception(s).
The remaining dependent claims, aside from claim 3, are directed to the type of breast cancers, further subsets of T cells, the patient, patient characteristics (other levels), mathematic calculations (i.e., a judicial exception), a type of expression level, or a sample type/subset. Limiting the data on which the judicial exception(s) are practiced is not sufficient to integrate the claim into a practical application. See MPEP 2106.04(d)(I) and 2105.05(g).
Claim 3 recites a step of administering a therapy. However, this limitation fails to integrate the claim into a practical application described in MPEP 2106.04(d)(2) at least because it encompasses mere extra-solution activity. The order of steps is not required by the claim language, and importing such from the specification would be improper. See MPEP 2111.01(II). As such, the administering the chemotherapeutic agent encompasses necessary treatment in order to perform data gathering for the judicial exception(s), i.e., to assess the impact of chemotherapeutic therapies on the levels of this population of T cells.
Regarding claims 5 and 43-44, as discussed in claim 3 above, the language of the administering a therapy step is not grammatically restricted to occurring subsequent to the detection. As such, the order is interpreted broadly to encompass the administering prior to the detection. As such, the administration of the therapy fails to integrate the claim into a practical application because it encompasses mere extra-solution activity. See MPEP 2106.04(d)(2).
Regarding claims 19, 20, 23, and 30, claim 19 recites detecting either an increased level (in step (i)) or a decreased level (in step (ii)) relative to a control. Claim 20 recites that step (i) further comprises administering a chemotherapeutic therapy; and step (ii) further comprises administer a non-chemotherapeutic therapy. The specification defines a “non-chemotherapeutic therapy” in para [0138], wherein it may encompass any compound, composition, combination therapy, treatment plan, or treatment regime that does not include chemo. This encompasses treatments that are not specific or particular to the judicial exception, such as aspirin to control pain or to prevent blood clots. See MPEP 2106.04(d)(2).
The remaining dependent claims are directed to mathematical calculations (i.e., a judicial exception) or a type of breast cancer, wherein it is likewise noted that limiting the data on which the judicial exception(s) are practiced is not sufficient to integrate the claim into a practical application. See MPEP 2106.04(d)(I) and 2105.05(g).
Step 2B. Does the claim amount to significantly more?
No. The claims currently encompass detecting a level of a biomarker in any sample type. The courts have found such to be mere data gathering. e.g., Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis).
Detecting a level of T cells in a sample from a breast cancer patient is likewise well-understood and conventional. Gao (Gao G, et al. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer. 2020 Mar 4;20(1):179; as cited in the IDS dated 05/02/2024) teaches at least 37 articles that assessed tumor infiltrating leukocyte levels (Fig. 1; Table 1; see also Background, para 2).
It is further noted that regardless of any novelty of a gene set, as described in MPEP 2106.05(I), “an inventive concept ‘cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself.’” Thus, calculation involving even novel gene sets or a novel calculation cannot amount to significantly more.
As discussed above, limitations that amount to selecting a particular data source to be utilized in the judicial exception are insignificant extra-solution activity.
Where treatment limitations are provided, they encompass extra-solution activity claimed broadly and encompassing well known and conventional therapies for breast cancer, (Waks AG, Winer EP. Breast Cancer Treatment: A Review. JAMA. 2019 Jan 22;321(3):288-300: Table 2: “Common Treatments”).
For these reasons, the claims as a whole do not amount to significantly more.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 2-3, 5, 8, 9, 34, and 36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584.).
Regarding claim 2, Terranova-Barberio teaches an exhausted CD8+ T-cell immune signature may predict response to immune checkpoint inhibitors (pg. 4, Discussion, spanning pg. 5), wherein exhausted T-cell infiltration robustly correlated with response rate [i.e., elevated levels indicate better response]. (pg. 5, col 1, para 1).
Regarding claims 3 and 5, Terranova-Barberio teaches that the treatment combined the immune checkpoint inhibitor and vorinostat [a chemotherapeutic] (pg. 2, col 2, para 1), wherein proportion of responders and duration of response was markedly improved in patients with an increased number of exhausted cytotoxic CD8+ T lymphocytes (pg. 3, col 1, para 1).
Regarding claim 8, Terranova-Barberio teaches that the patients of the study have ER+ breast cancer (entire document, e.g., Title; Abstract; pg. 2, col 2, para 3).
Regarding claim 9, Terranova-Barberio teaches that the study included pre-menopausal women (pg. 6, Patient selection).
Regarding claim 34, Terranova-Barberio teaches an immunophenotyping panel using flow cytometry to determine cell populations (pg. 8, col 2, para 1-2), wherein gating is based on protein expression (e.g., Fig. 2c).
Regarding claim 36, Terranova-Barberio teaches that the samples comprise pre and post treatment biopsies of metastatic sites [i.e., tumor] (pg. 8, col 2, para 1-2).
For at least these reasons, claims 2-3, 5, 8, 9, 34, and 36 are anticipated by Terranova-Barberio.
Claim(s) 19-20 and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Solomayer (Solomayer EF, et al. Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clin Cancer Res. 2003 Jan;9(1):174-80.)
Regarding claim 19, Solomayer teaches detecting a reduced the amount of CD4+CD26+ T cells in chemotherapy-treated patients compared with an untreated group in bone marrow (pg. 176, col 2, para 1), wherein 10 of the 17 patients had evidence of disseminated tumor cells in the bone marrow samples (pg. 177, col 2, para 1) and breast cancer cells are known to develop BM micrometastes (pg. 174, col 2, para 2).
Regarding claim 20, Solomayer teaches that the patients in the chemotherapy group were administered standard chemotherapy [i.e., effective dosages/cycles] (pg. 175, Characteristics of the Patients).
Regarding claim 30, Solomayer teaches that the breast cancers comprise ER+ positive breast cancers (Table 1).
For at least these reasons, claims 19-20 and 30 are anticipated by Solomayer.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 10-11, 13, 43, and 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584.) as applied to claims 2 and 5 above and further in view of Solomayer (Solomayer EF, et al. Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clin Cancer Res. 2003 Jan;9(1):174-80.)
Regarding claims 10 and 11, in the method of Terranova-Barberio, Terranova-Barberio teaches a depletion of CD4+ Treg (Foxp3+) cells was seen in tumor or blood in patient with clinical benefit to the combined immunotherapy and chemotherapy treatment (Abstract and pg. 3, Epigenetic modulation of CD4+ regulatory T-cells (Tregs) and histone acetylation; see also pg. 2, col 2, para 1), and the reduction was significant in activated Tregs in the tumor microenvironment, wherein preclinical data suggested this was due to the vorinostat [chemotherapeutic] treatment (pg. 3, col 2, para 5).
Terranova-Barberio teaches that the goal is to determine whether the coadministration of its treatment can convert immune silent ER-positive breast cancers into an immune responsive phenotype and define any signatures of response (pg. 2, col 2, para 1).
Terranova-Barberio also teaches prior administration of a chemotherapy (Table 1).
However, Terranova-Barberio fails to teach that the depletion is CD26+CD4+ T cells.
Solomayer rectifies this by teaching that chemotherapy reduced the amount of CD4+CD26+ T cells in chemotherapy treated patients compared with an untreated group in bone marrow (pg. 176, col 2, para 1), wherein 10 of the 17 patients had evidence of disseminated tumor cells in the bone marrow samples (pg. 177, col 2, para 1) and breast cancer cells are known to develop BM micrometastes (pg. 174, col 2, para 2).
Solomayer teaches that the level of post-chemotherapy counts shows evidence of reduced potential for direct antitumor reactivity (pg. 177, col 2, para 4), wherein such influences the prognosis of patients and a better cell-mediated immunity may offer a protective effect against metastatic development (pg. 179, col 1, para 2). Solomayer teaches that the loss in the proportion of activated (CD26) CD4 T helper cells may exert negative influence on the CD8 T-cell pool (pg. 179, col 2, para 2).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to additionally look for the CD26+CD4+ T cells of Solomayer in the method of Terranova-Barberio, motivated by the desire to observe the influences of antitumor reactivity in order to better assess the prognosis of patients via cell-mediated immunity, as taught by Solomayer. Additionally or alternative, it would have been obvious to assess these immune cells of Solomayer to assist in better determining whether the treatment is effective at converting immune silent ER-positive breast cancers into an immune responsive phenotype, as taught by Solomayer. There would have been a strong expectation for success as both are directed to treating breast cancers and observing cell levels, and such represents the application of a known method to a known technique.
Regarding claim 13, in the method of Terranova-Barberio in view of Solomayer, Terranova-Barberio teaches that the patients of the study have ER+ breast cancer (entire document, e.g., Title; Abstract; pg. 2, col 2, para 3).
Solomayer teaches ER+ and PR+ cancers (Table 1).
Regarding claims 43 and 44, in the method of Terranova, Terranova-Barberio teaches HDACi vorinostat, which is an epigenetic modifier rather than the classes of chemotherapies of claims 43 and 44. Terranova-Barberio teaches that the patients were heavily pre-treated breast cancer patients who had received at least one dose of therapy, with 85% having received at least 3 lines of therapy (pg. 2, col 2, para 3).
Thus, Terranova-Barberio teaches that the patients were administered a therapy prior to the study but not explicitly that it was one of the claimed chemotherapeutic agents.
Solomayer rectifies this by teaching that the patients were administered a standard chemotherapy comprising 5-fluorouracil, methotrexate, cyclophosphamide, and/or epirubicin (pg. 175, col 1, Characteristics of the Patients). Solomayer teaches that CHT is a standard adjuvant prophylaxis against disseminated tumor cells (pg. 174, col 2, para 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the method of Terranova-Barberio in view of Solomayer comprising detecting exhausted CD8+ cells on patients to whom the above chemotherapies are administered [i.e., prior to detection], motivated by the desire to target disseminated tumor cells, as taught by Solomayer, and to utilize the method as part of a standard of care therapy. There would have been a strong expectation of success as both are directed to treatment of breast cancers and monitoring immune cells, wherein such represents the application of a known technique to a known method.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584.) as applied to claim 2 above, and further in view of Syed Khaja (Syed Khaja AS, et al. Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment. Oncotarget. 2017 May 16;8(20):33159-33171).
Regarding claim 6, in the method of Terranova-Barberio, Terranova- Barberio teaches using the CD8+ T-cell exhaustion markers PD-1 and CTLA-4 (entire document, e.g., Abstract), thus failing to teach that the CD8+ T cells are CD39.
Syed Khaja rectifies this by teaching a terminally exhausted phenotype of CD8+ T cells in breast cancer assessed by CD39 and PD-1 expression (Abstract). Syed Khaja teaches that CD8+ T cells in the tumor micro environment express high levels of CD39, indicating their terminal exhaustive state (pg. 33165, col 2, para 1, spanning pg. 33166) and that expression of CTLA-4 and PD-1 was negligible in CD8+ T cells(pg. 33161, col 1, para 1, spanning pg. 33162; Fig. 5D).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to simply substitute the PD-1 and CD39 markers of Syed Khaja in the method of Terranova-Barberio of detecting exhausted CD8+ T cells, motivated by the desire to be able to identify a greater number of cells, as taught by Syed Khaja, in order to develop a more robust signature. There would have been a strong expectation of success as both are directed to determining tumor infiltrating immune subsets in breast cancer, especially for treatment, and such represents the application of a known signature to a known method.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584 as applied to claim 2 above, and further in view of Jerby-Arnon (US 2021/0130438 A1; published 05/06/2021) and Warren (WO 2019/226514 A2; published 11/28/2019).
Regarding claim 7, in the method of Terranova-Barberio, Terranova-Barberio fails to teaches a level of exhausted CD8+ T cells determined by a weighted average of the elevated expression level of the genes in Table 1.
Jerby-Arnon rectifies this by teaching a method of detecting dysfunctional [i.e., exhausted] T cells comprising detecting a dysfunctional gene signature in T cells obtained from a subject in need thereof, wherein the signature comprises expression of (claim 31):
a. one or more of the group selected from the group consisting of: CD82, CXLC13, HLA-DRA, HLA-DRB1, BST2, IFI6, ISG15, MX1, … and HLA-DRB5; or
b. one or more of the group selected from the group consisting of: LY6E, … and MX1; or
f. one or more of the genes selected from the group consisting of: CXCL13, … and ISG15, further comprises expression of one or more genes selected from the group consisting of HAVCR2, … and ENTPD1.
As discussed previously, an unequally weighted may consist of one gene with a weight and all other genes with zero weights. Thus, by teaching a signature with at least one of the genes of Table 1, the limitation, broadly interpreted, is taught.
Jerby-Arnon teaches that the data utilized comes, in part, from breast cancer (para [0052]).
Jerby-Arnon teaches that the markers generalize across cancer types, are evolutionarily conserved, and accurately predict the subsequent clinical response and capture aspects of T cell dysfunction that are not fully reversed by CTLA-4 and PD-1 blockade (para [0052]).
Warren teaches a process of training optimize weight for a set of p signature genes (para [00184]) based on the log2 expression values of the p selected genes (para [00185]), wherein the signature is a weighted average of its expression genes (para [00191]) and the weights are an average of the resulting weight vectors optimized across the training datasets (para [00197]).
Warren teaches that the weights sum to 1 and by placing each signature on the log2 scale, a unit increase corresponds to roughly a doubling of signature gene expression (para [00191]).
Warren teaches optimizing signatures through training of models (para [00200-208]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the signature of Jerby-Arnon in the method of Terranova-Barberio, motivated by the desire to predict clinical response and capture additional aspect of T cell dysfunction/exhaustion, as taught by Jerby-Arnon, so as to improve patient outcomes. There would have been a strong expectation of success as both are directed to identifying immune cells relevant to treatment, including in breast cancers, and such represents the application of a known technique to a known method.
Further, for the sake of argument, it would have been obvious to the artisan before the ERD to further utilize the weighting and optimization of Warren in applying the signature of Jerby-Arnon in the method of Terranova-Barberio, motivated by the desire to develop a score that utilizes a weighting and expression scale scheme that results in a unit increase corresponding to a rough doubling, as taught by Warren, so as to develop a score that is easy to practitioners to understand. There would have been a strong expectation of success as Warren is also directed to identifying immune cells in a patient with cancer for determining treatment, and such represents the application of a known technique to a known method.
It is further noted that particular weights and the number of genes would be subject to routine optimization based on the data of the training sets, as taught by Warren. See MPEP 2144.05(II).
Claim(s) 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584.) as applied to claim 2 above, and further in view of Ibraheem (Ibraheem AF, et al. Community clinical practice patterns and mortality in patients with intermediate oncotype DX recurrence scores: Who benefits from chemotherapy? Cancer. 2019 Jan 15;125(2):213-222. Epub 2018 Nov 2), as evidenced by Paik (Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004 Dec 30;351(27):2817-26)
Regarding claim 37, in the method of Terranova-Barberio, Terranova-Barberio teaches hormone receptor positive cancers and that some therapies are ineffective for hormone receptor positive breast cancers (pg. 2, col 1, para 1). Terranova-Barberio teaches evaluating patients in a prospective trial (pg. 6, col 1, para 1, spanning col 2).
Terranova-Barberio fails to teach assessing the biological samples for the gene list of claim 37 or the gene expression level of each gene.
Ibraheem rectifies this by teaching that Oncotype DX RS is a tool for making decisions about chemotherapy for patients who have hormone receptor positive breast cancer (Abstract), wherein receipt of chemotherapy was associated with reduced risk of death among patients who had lymph node-positive breast cancer and benefit from chemo who have an intermediate risk score is driven in a nonlinear fashion, such that the higher the RS, the larger the absolute benefit (Abstract)
While Ibraheem does not explicitly teach the list, it is inherently taught because the set of genes is the set of “test” genes of the Oncotype DX test, as evidenced by Ibraheem (Introduction, para. 2), which teaches the name and that it is the test of Paik (Fig. 1: Gene List).
Therefore, it would have been obvious to one of skill in the art before the effective filing date to utilize the Oncotype DX (B)RS gene set in screening patients for the prospective trial of the method of Terranova-Barberio, motivated by the desire to effectively teat the lymph-node positive hormone receptor-positive intermediate patients taught to benefit from chemotherapy in Ibraheem. There would have been a strong expectation of success as both are directed to assigning patients to subsets for more effective treatments of breast cancers, and such represents the application of a known technique to a known method.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Terranova-Barberio (Terranova-Barberio M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584.) in view of Solomayer (Solomayer EF, et al. Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clin Cancer Res. 2003 Jan;9(1):174-80.) as applied to claim 10 above, and further in view of Jerby-Arnon (US 2021/0130438 A1; published 05/06/2021), Bailey (Bailey SR, et al. Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat Commun. 2017 Dec 6;8(1):1961), and Warren (WO 2019/226514 A2; published 11/28/2019), as evidenced by NCBI (IL7R interleukin 7 receptor [homo sapiens (human)] - gene - NCBI [Internet]. U.S. National Library of Medicine; [cited 2025 Dec 13]. Available from: https://www.ncbi.nlm.nih.gov/gene/3575).
Regarding claim 12, in the method of Terranova-Barberio in view of Solomayer, Terranova-Barberio fails to teaches a level of exhausted CD8+ T cells determined by a weighted average of the elevated expression level of the genes in Table 1.
Solomayer teaches that it is not clear if tumor-reactive memory T-cell pools are preserved upon chemotherapy and is interested in the relative rates of naïve and memory CD4+ cells (pg. 179, col 1, para 1).
Solomayer fails to teach the gene expression signature of Table 2.
Jerby-Arnon rectifies this in part by teaching a method of detecting dysfunctional [i.e., exhausted] T cells comprising detecting a dysfunctional gene signature in T cells obtained from a subject in need thereof, wherein the signature comprises expression of (claim 31):
a. one or more of the group selected from the group consisting of: CD82, CXLC13, HLA-DRA, HLA-DRB1, BST2, IFI6, ISG15, MX1, … and HLA-DRB5; or
b. one or more of the group selected from the group consisting of: LY6E, … and MX1; or
f. one or more of the genes selected from the group consisting of: CXCL13, … and ISG15, further comprises expression of one or more genes selected from the group consisting of HAVCR2, … and ENTPD1.
As discussed previously, an unequally weighted may consist of one gene with a weight and all other genes with zero weights. Thus, by teaching a signature with at least one of the genes of Table 1, the limitation, broadly interpreted, is taught.
Jerby-Arnon teaches that the data utilized comes, in part, from breast cancer (para [0052]).
Jerby-Arnon teaches that the markers generalize across cancer types, are evolutionarily conserved, and accurately predict the subsequent clinical response and capture aspects of T cell dysfunction that are not fully reversed by CTLA-4 and PD-1 blockade (para [0052]).
Bailey further rectifies this by teaching CD127 as a phenotypic marker CD26_high CD4+ T cells (Fig. 3A) and KLRB1 as a marker of the Th1/Th17 subtype of CD26+CD4+ T cells (Fig. 3C; pg. 5, col 1, para 1, spanning col 2). Bailey teaches that CD26 expression correlates with specific CD4+ T cell subsets (pg. 5, col 1, para 1, spanning col 2), wherein CD26_high cells displayed a Th1/Th17 profile (pg. 10, col 1, para 3). Bailey teaches utilizing CD26 as a biomarker for therapies (pg. 10, col 2, para 1 and 3; pg. 11, col 1, para 2). Bailey teaches that CD26_int cells have a naïve phenotype and CD26_high cells have a durable memory, enabling them to persist and regress multiple solid tumors (pg. 11, col 1, para 2).
Bailey teaches IL7R by teaching CD127 (Fig. 3A), evidenced by NCBI. While Bailey doesn’t explicitly teach IL7R, it is inherently taught because CD127 is an alternative name for IL7R (NCBI: Also known as).
Warren additionally teaches a process of training optimize weight for a set of p signature genes (para [00184]) based on the log2 expression values of the p selected genes (para [00185]), wherein the signature is a weighted average of its expression genes (para [00191]) and the weights are an average of the resulting weight vectors optimized across the training datasets (para [00197]).
Warren teaches that the weights sum to 1 and by placing each signature on the log2 scale, a unit increase corresponds to roughly a doubling of signature gene expression (para [00191]).
Warren teaches optimizing signatures through training of models (para [00200-208]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the signature of Jerby-Arnon in the method of Terranova-Barberio in view of Solomayer, motivated by the desire to predict clinical response and capture additional aspect of T cell dysfunction/exhaustion, as taught by Jerby-Arnon, so as to improve patient outcomes. There would have been a strong expectation of success as all are directed to identifying immune cells relevant to treatment, including in breast cancers, and such represents the application of a known technique to a known method.
It likewise would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize at least the Th1/Th17 CD26+CD4+ T cell signature of Bailey in the method of Terra-Barberio in view of Solomayer and Jerby-Arnon, motivated by the desire to further subset CD26+CD4+ into high and low expressing subtypes based on their propensity to have a meaningful impact on cancer regression, as taught by Bailey, so as to improve patient outcomes. It follows that as the markers of Bailey are increased, and Solomayer shows that the cells are decreased, the subsets measured by the gene expression would also be decreased relative to the same control(s). There would have been a strong expectation of success as all are directed to identifying immune cells relevant to treatment in solid tumors, and such represents the application of a known technique to a known method.
Further, for the sake of argument, it would have been obvious to the artisan before the ERD to further utilize the weighting and optimization of Warren in applying the signatures of Jerby-Arnon and Bailey in the combined method, motivated by the desire to develop a score that utilizes a weighting and expression scale scheme that results in a unit increase corresponding to a rough doubling, as taught by Warren, so as to develop a score that is easy to practitioners to understand. There would have been a strong expectation of success as Warren is also directed to identifying immune cells in a patient with cancer for determining treatment, and such represents the application of a known technique to a known method.
It is further noted that particular weights and the number of genes would be subject to routine optimization based on the data of the training sets, as taught by Warren. See MPEP 2144.05(II).
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Solomayer (Solomayer EF, et al. Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer. Clin Cancer Res. 2003 Jan;9(1):174-80.) as applied to claim 2 above, and further in view of Bailey (Bailey SR, et al. Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat Commun. 2017 Dec 6;8(1):1961) and Warren (WO 2019/226514 A2; published 11/28/2019), as evidenced by NCBI (IL7R interleukin 7 receptor [homo sapiens (human)] - gene - NCBI [Internet]. U.S. National Library of Medicine; [cited 2025 Dec 13]. Available from: https://www.ncbi.nlm.nih.gov/gene/3575).
Regarding claim 23, in the method of Solomayer, Solomayer teaches that it is not clear if tumor-reactive memory T-cell pools are preserved upon chemotherapy and is interested in the relative rates of naïve and memory CD4+ cells (pg. 179, col 1, para 1).
Solomayer fails to teach the gene expression signature of Table 2.
Bailey rectifies this by teaching CD127 as a phenotypic marker CD26_high CD4+ T cells (Fig. 3A) and KLRB1 as a marker of the Th1/Th17 subtype of CD26+CD4+ T cells (Fig. 3C; pg. 5, col 1, para 1, spanning col 2). Bailey teaches that CD26 expression correlates with specific CD4+ T cell subsets (pg. 5, col 1, para 1, spanning col 2), wherein CD26_high cells displayed a Th1/Th17 profile (pg. 10, col 1, para 3). Bailey teaches utilizing CD26 as a biomarker for therapies (pg. 10, col 2, para 1 and 3; pg. 11, col 1, para 2). Bailey teaches that CD26_int cells have a naïve phenotype and CD26_high cells have a durable memory, enabling them to persist and regress multiple solid tumors (pg. 11, col 1, para 2).
Bailey teaches IL7R by teaching CD127 (Fig. 3A), evidenced by NCBI. While Bailey doesn’t explicitly teach IL7R, it is inherently taught because CD127 is an alternative name for IL7R (NCBI: Also known as).
Warren teaches a process of training optimize weight for a set of p signature genes (para [00184]) based on the log2 expression values of the p selected genes (para [00185]), wherein the signature is a weighted average of its expression genes (para [00191]) and the weights are an average of the resulting weight vectors optimized across the training datasets (para [00197]).
Warren teaches that the weights sum to 1 and by placing each signature on the log2 scale, a unit increase corresponds to roughly a doubling of signature gene expression (para [00191]).
Warren teaches optimizing signatures through training of models (para [00200-208]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize at least the Th1/Th17 CD26+CD4+ T cell signature of Bailey in the method of Solomayer, motivated by the desire to further subset CD26+CD4+ into high and low expressing subtypes based on their propensity to have a meaningful impact on cancer regression, as taught by Bailey, so as to improve patient outcomes. It follows that as the markers of Bailey are increased, and Solomayer shows that the cells are decreased, the subsets measured by the gene expression would also be decreased relative to the same control(s). There would have been a strong expectation of success as both are directed to identifying immune cells relevant to treatment in solid tumors, and such represents the application of a known technique to a known method.
Further, for the sake of argument, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further utilize the weighting and optimization of Warren in applying the signature of Bailey in the method of Terranova-Barberio, motivated by the desire to develop a score that utilizes a weighting and expression scale scheme that results in a unit increase corresponding to a rough doubling, as taught by Warren, so as to develop a score that is easy to practitioners to understand. There would have been a strong expectation of success as Warren is also directed to identifying immune cells in a patient with cancer for determining treatment, and such represents the application of a known technique to a known method.
It is further noted that particular weights and the number of genes would be subject to routine optimization based on the data of the training sets, as taught by Warren. See MPEP 2144.05(II).
Conclusion
No claims are allowed.
This Office action has an attached requirement for information under 37 CFR 1.105. A complete reply to this Office action must include a complete reply to the attached requirement for information. The time period for reply to the attached requirement coincides with the time period for reply to this Office action.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Egelston – STIC – 2018 (Egelston C, et al. The presence of exhausted CD8+ T cells identifies a subset of immunogenic ER+ breast cancer patient tumors. Journal for ImmunoTherapy of Cancer. 2018 Nov;6(S1):22–22.) teaches detecting PD-1+ CD-39+ CD8+ T cells in ER+ and TNBC at a “significant frequency” and that ER+ tumors with said exhausted T cells were significantly more infiltrated with T cells (Results). Egelston – STIC – 2018 teaches an RNA transcript gene signature for ER+ tumors containing said exhausted T cells (Results), wherein said patients may have a tumor antigen driven response and may benefit from related interventions (Conclusions).
Egleston – STIC - 2019 (Egelston C, et al. A transcriptional signature of exhausted CD8+ T cells predicts relapse-free outcome in ER+ breast cancer patients. Journal for ImmunoTherapy of Cancer. 2019 Nov;7(S1):26–26.) teaches identifying exhausted CD8+ T cells in ER+ and TNBC (Results) and developing a signature score based on transcriptional profiles developed from single cell sequencing of sorted T cells (Methods), including exhausted CD8+ T cells (Results). Egleston – STIC – 2019 suggests treating with chemotherapy in the presence of TILs (Background).
Egelston – Immunology – 2018 (Egelston C, et al. Complex phenotyping of PD-1+ CD39+ exhausted CD8+ T cells in human carcinomas. The Journal of Immunology. 2018 May 1;200(Supplement_1)) teaches detecting PD-1+ CD39+ exhausted T cells in solid tumors, tumor positive tumor draining lymph nodes, and one CLL patient, but not identified in the circulation or tumor negative tumor draining lymph nodes of patients [i.e., elevated in one sample relative to a control] and that single cell sequencing revealed a distinct transcriptional signature of PD-1+ CD39+ CD8+ T cells.
Egelston – Immunology – 2019 (Egelston C, et al. Identification of exhausted CD8+ T cells in low tumor mutation burden breast cancer patients. The Journal of Immunology. 2019 May 1;202(1_Supplement)) teaches that subsets of both triple negative and estrogen receptor positive breast cancer patients have primary tumors heavily infiltrated by tumor specific exhausted CD8+ TILs (TILex), wherein CD8+ TILex in breast cancer coexpress PD-1 and CD39 and have a shared transcriptional signature identified by single cell sequencing. Egelston – Immunology – 2019 suggests treating with particular interventions.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636